GNAO1 encephalopathy: further delineation of a severe neurodevelopmental syndrome affecting females

Marcé‐Grau, Anna; Dalton, James A. R.; Pisón, J. López; García-Jiménez, M.C.; Galindo, L. Monge; Cuenca-León, Ester; Giraldo, Jesús; Macaya, Alfons

doi:10.1186/s13023-016-0416-0

Cited by 41 publications

(43 citation statements)

References 28 publications

(34 reference statements)

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“…[2][3][4][5]8,10,12,[14][15][16]26 MRI studies have not shown major structural abnormalities in patients with GNAO1 variants. Developmental delay and hypotonia occur in nearly all cases, although they led less frequently to medical attention.…”

Section: Discussionmentioning

confidence: 99%

“…[2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] GNAO1 encodes a G-protein α subunit that, along with dimerized β and γ subunits, forms a heterotrimeric G-protein complex. [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] GNAO1 encodes a G-protein α subunit that, along with dimerized β and γ subunits, forms a heterotrimeric G-protein complex.…”

Section: Introductionmentioning

confidence: 99%

“…GNAO1, or guanosine nucleotide-binding protein G(o) subunit α, is a gene that has been associated with neurodevelopmental disorders, including early onset developmental and epileptic encephalopathy (DEE), 1 developmental delay without epilepsy, and a range of movement disorders. [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] GNAO1 encodes a G-protein α subunit that, along with dimerized β and γ subunits, forms a heterotrimeric G-protein complex. G-protein α subunits contain guanosine triphosphate (GTP)-binding sites and dissociate from both the G-protein-coupled receptor and the β-γ dimer of the complex when activated.…”

Section: Introductionmentioning

confidence: 99%

“…GNAO1 encodes an "o" type α subunit; beyond GTP binding, it has a less well-established role in signaling. 10 GNAO1 is highly expressed in the central nervous system and is involved in neuronal excitability and neurotransmission. 2,10 Here, we report 14 previously unpublished patients with heterozygous, de novo GNAO1 variants classified as pathogenic or likely pathogenic, including one variant shared by two siblings attributable to parental mosaicism.…”

Section: Introductionmentioning

confidence: 99%

“…10 GNAO1 is highly expressed in the central nervous system and is involved in neuronal excitability and neurotransmission. 2,10 Here, we report 14 previously unpublished patients with heterozygous, de novo GNAO1 variants classified as pathogenic or likely pathogenic, including one variant shared by two siblings attributable to parental mosaicism. Two key components of our in silico variant analyses were the comparison of variants in our cohort with those present in the general population and the variant location on the predicted GNAO1 protein structure.…”

Section: Introductionmentioning

confidence: 99%

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Spectrum of neurodevelopmental disease associated with the GNAO1 guanosine triphosphate–binding region

et al. 2019

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Summary Objective To characterize the phenotypic spectrum associated with GNAO1 variants and establish genotype‐protein structure‐phenotype relationships. Methods We evaluated the phenotypes of 14 patients with GNAO1 variants, analyzed their variants for potential pathogenicity, and mapped them, along with those in the literature, on a three‐dimensional structural protein model. Results The 14 patients in our cohort, including one sibling pair, had 13 distinct, heterozygous GNAO1 variants classified as pathogenic or likely pathogenic. We attributed the same variant in two siblings to parental mosaicism. Patients initially presented with seizures beginning in the first 3 months of life (8/14), developmental delay (4/14), hypotonia (1/14), or movement disorder (1/14). All patients had hypotonia and developmental delay ranging from mild to severe. Nine had epilepsy, and nine had movement disorders, including dystonia, ataxia, chorea, and dyskinesia. The 13 GNAO1 variants in our patients are predicted to result in amino acid substitutions or deletions in the GNAO1 guanosine triphosphate (GTP)‐binding region, analogous to those in previous publications. Patients with variants affecting amino acids 207‐221 had only movement disorder and hypotonia. Patients with variants affecting the C‐terminal region had the mildest phenotypes. Significance GNAO1 encephalopathy most frequently presents with seizures beginning in the first 3 months of life. Concurrent movement disorders are also a prominent feature in the spectrum of GNAO1 encephalopathy. All variants affected the GTP‐binding domain of GNAO1, highlighting the importance of this region for G‐protein signaling and neurodevelopment.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Spectrum of neurodevelopmental disease associated with the GNAO1 guanosine triphosphate–binding region

et al. 2019

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Severity of GNAO1‐Related Disorder Correlates with Changes in G‐Protein Function

Domínguez‐Carral,

Ludlam,

Junyent Segarra

et al. 2023

Annals of Neurology

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ObjectiveGNAO1‐related disorders (OMIM #615473 and #617493), caused by variants in the GNAO1 gene, are characterized by developmental delay or intellectual disability, hypotonia, movement disorders, and epilepsy. Neither a genotype–phenotype correlation nor a clear severity score have been established for this disorder. The objective of this prospective and retrospective observational study was to develop a severity score for GNAO1‐related disorders and to delineate the correlation between the underlying molecular mechanisms and clinical severity.MethodsSixteen individuals with GNAO1‐related disorders harboring 12 distinct missense variants, including four novel variants (p.K46R, p.T48I, p.R209P, and p.L235P) were examined with repeated clinical assessments, video‐EEG monitoring, and brain MRI. The molecular pathology of each variant was delineated using a molecular deconvoluting platform.ResultsThe patients displayed a wide variability in the severity of their symptoms. This heterogeneity was well represented in the GNAO1‐related disorders severity score, with a broad range of results. Patients with the same variant had comparable severity scores, indicating that differences in disease profiles are not due to inter‐patient variability but rather to unique disease mechanisms. Moreover, we found a significant correlation between clinical severity scores and molecular mechanisms.InterpretationThe clinical score proposed here provides further insight into the correlation between pathophysiology and phenotypic severity in GNAO1‐related disorders. We found that each variant has a unique profile of clinical phenotypes and pathological molecular mechanisms. These findings will contribute to better understanding GNAO1‐related disorders. Additionally, the severity score will facilitate standardization of patients categorization and assessment of response to therapies in development.This article is protected by copyright. All rights reserved.

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Clinical and Molecular Profiling in GNAO1 Permits Phenotype–Genotype Correlation

Lasa‐Aranzasti,

Larasati,

da Silva Cardoso

et al. 2024

Movement Disorders

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BackgroundDefects in GNAO1, the gene encoding the major neuronal G‐protein Gαo, are related to neurodevelopmental disorders, epilepsy, and movement disorders. Nevertheless, there is a poor understanding of how molecular mechanisms explain the different phenotypes.ObjectivesWe aimed to analyze the clinical phenotype and the molecular characterization of GNAO1‐related disorders.MethodsPatients were recruited in collaboration with the Spanish GNAO1 Association. For patient phenotyping, direct clinical evaluation, analysis of homemade‐videos, and an online questionnaire completed by families were analyzed. We studied Gαo cellular expression, the interactions of the partner proteins, and binding to guanosine triphosphate (GTP) and G‐protein‐coupled receptors (GPCRs).ResultsEighteen patients with GNAO1 genetic defects had a complex neurodevelopmental disorder, epilepsy, central hypotonia, and movement disorders. Eleven patients showed neurological deterioration, recurrent hyperkinetic crisis with partial recovery, and secondary complications leading to death in three cases. Deep brain stimulation improved hyperkinetic crisis, but had inconsistent benefits in dystonia. The molecular defects caused by pathogenic Gαo were aberrant GTP binding and hydrolysis activities, an inability to interact with cellular binding partners, and reduced coupling to GPCRs. Decreased localization of Gαo in the plasma membrane was correlated with the phenotype of “developmental and epileptic encephalopathy 17.” We observed a genotype–phenotype correlation, pathogenic variants in position 203 were related to developmental and epileptic encephalopathy, whereas those in position 209 were related to neurodevelopmental disorder with involuntary movements. Milder phenotypes were associated with other molecular defects such as del.16q12.2q21 and I344del.ConclusionWe highlight the complexity of the motor phenotype, which is characterized by fluctuations throughout the day, and hyperkinetic crisis with a distinct post‐hyperkinetic crisis state. We confirm a molecular‐based genotype–phenotype correlation for specific variants. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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GNAO1 encephalopathy: further delineation of a severe neurodevelopmental syndrome affecting females

Cited by 41 publications

References 28 publications

Spectrum of neurodevelopmental disease associated with the GNAO1 guanosine triphosphate–binding region

Spectrum of neurodevelopmental disease associated with the GNAO1 guanosine triphosphate–binding region

Severity of GNAO1‐Related Disorder Correlates with Changes in G‐Protein Function

Clinical and Molecular Profiling in GNAO1 Permits Phenotype–Genotype Correlation

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